1. Field of the Invention
The present invention relates to the synthesis of novel ligands selective for a subgroup of receptors for serotonin (5-HT). While there are seven subgroups of 5-HT receptors, this invention is selective for the 5-HT6 subgroup. This invention also relates to the synthesis of novel ligands selective for the 5-HT6 subgroup receptor that act as agonists to the natural ligands for this receptor. The invention also relates to the creation of novel ligands that act as antagonists to the 5-HT6 receptor. The invention further relates to use of said compounds to treat mammals adversely affected by conditions mediated by the 5-HT6 receptor.
2. Description of the Prior Art
Serotonin receptors have been divided into a number of families and subfamilies (5-HT1-5-HT7) and approximately 14 populations have been cloned. One of the newest populations identified is the 5-HT6 subgroup. It has been observed that various tricyclic psychotropic agents (neuroleptics, antidepressants, and atypical neuroleptics agents) bind the 5-HT6 receptor with nanomolar affinities (Roth et al. J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410). A rat 5-HT6 receptor was first cloned in 1993 and, more recently, the same group described the cloning of a human 5-HT6 receptor. The 5-HT6 serotonin receptors are members of the G-protein superfamily, are positively coupled to an adenylate cyclase second messenger system. and are found primarily in the central nervous system. Serotonin bound to the 5-HT6 receptor subgroup causes an activation of the adenylate cyclase enyme, with concomitant increased levels of intracellular cAMP. Although the exact physiological function and clinical significance of the 5-HT6 receptor subgroup is not known, as noted above, many anti-psychotic agents bind these receptors with high affinity. Also, in rats that do not express 5-HT6 receptors, the animals behave in a manner that seems to involve an increase in cholinergic function, suggesting that 5-HT6 specific ligands might be of value in the treatment of anxiety-related disorders and memory deficits.
Upon binding to cellular receptors, ligands may act as agonists or antagonists to endogenous receptor-ligand function. In the case of the 5-HT6 receptor, several specific ligands have been discovered which act as 5-HT6 specific antagonists, but prior to the present invention, selective ligands which act as agonists to the 5-HT6 receptor were unknown.
It is an object of the invention to create derivatives of serotonin (5-HT) that specifically bind the 5-HT6 receptor subgroup of the serotonin receptor family. It is another object of this invention to create 5-HT6-selective ligands that act as agonists when bound to the 5-HT6 receptor. It is further an object of this invention to create 5-HT6-selective ligands that act as antagonists when bound to the 5-HT6 receptor. Furthermore, the compounds of the present invention that possess antagonist activity are tryptamine derivatives and are structurally unrelated to previously described 5-HT6 antagonists. It is further an object of this invention to administer 5-HT6 selective ligands to animals to determine the physiological and biochemical effects of specific activation and inhibition of 5-HT6 receptor function. Finally, it is an object of this invention to treat mental disorders mediated by 5-HT6 function by administering to treatment subjects the 5-HT6-selective agonists and antagonist compounds described herein.
Various indolealkylamines, including serotonin(5-HT) and 5-methoxytryptamine, have been observed to bind the 5-HT6 receptor with high affinity and produce a potent dose-dependent increase in cAMP levels. These tryptamines, however, are non-selective and bind at multiple families of 5-HT receptors. According to the invention, various modifications of 5-HT have been made to generate ligands with selectivity for the 5-HT6 receptor. An analog of 5-HT with a 2-methyl substituent introduced (2-methyly-5-HT) binds the 5-HT6 receptor with an affinity equivalent to that of the parent compound. The above analog is selective for the 5-HT6 and 5-HT3 receptors and binds at the 5-HT6 subgroup with a 20 fold greater affinity than at 5-HT3 receptors.
A 2-methyl analog of 5-methoxytryptamine, 5-methoxy-2-methyltryptamine, binds to the 5-HT6 receptor with an affinity comparable to 2-methyl-5-HT. However, 5-methoxy-2-methyltryptamine lacks affinity for 5-HT3 receptors. Thus, 5-methoxy-2-methyltryptamine presents a ligand with specificity for the 5-HT6 receptor subgroup. In the present invention, the 5-methoxy-2-methyltryptamine compound has been modified and several of its alkyl derivatives bind with comparable affinity and activate adenylate cyclase activity at levels comparable to serotonin. Furthermore, one derivative, 5-methoxy-2-phenylotryptamine, binds to the 5-HT6 receptor with a high affinity but the phenyl addition renders the compound an antagonist to 5-HT stimulated adenylate cyclase activity.